Adaptations in skeletal muscle mitochondria are considered to play an important role in the beneficial effect of exercise on metabolic control, while the contribution of adipose tissue is less clear.

Mitochondria are dynamic organelles with diverse functions in tissues such as liver and skeletal muscle. To unravel the mitochondrial contribution to tissue-specific physiology, we performed a systematic comparison of the mitochondrial proteome and lipidome of mice and assessed the consequences hereof for respiration. Liver and skeletal muscle mitochondrial protein composition was studied by data-independent ultra-high-performance (UHP)LC-MS/MS-proteomics, and lipid profiles were compared by UHPLC-MS/MS lipidomics. Mitochondrial function was investigated by high-resolution respirometry in samples from mice and humans. Enzymes of pyruvate oxidation as well as several subunits of complex I, III, and ATP synthase were more abundant in muscle mitochondria. Muscle mitochondria were enriched in cardiolipins associated with higher oxidative phosphorylation capacity and flexibility, in particular CL(18:2)4 and 22:6-containing cardiolipins. In contrast, protein equipment of liver mitochondria indicated a shuttling of complex I substrates toward gluconeogenesis and ketogenesis and a higher preference for electron transfer via the flavoprotein quinone oxidoreductase pathway. Concordantly, muscle and liver mitochondria showed distinct respiratory substrate preferences. Muscle respired significantly more on the complex I substrates pyruvate and glutamate, whereas in liver maximal respiration was supported by complex II substrate succinate. This was a consistent finding in mouse liver and skeletal muscle mitochondria and human samples. Muscle mitochondria are tailored to produce ATP with a high capacity for complex I-linked substrates. Liver mitochondria are more connected to biosynthetic pathways, preferring fatty acids and succinate for oxidation. The physiologic diversity of mitochondria may help to understand tissue-specific disease pathologies and to develop therapies targeting mitochondrial function.

TGFβ plays an important role in skeletal muscle by inhibiting cell differentiation and regulating inflammation and extracellular matrix production. Recent data link TGFβ with reduced expression of mitochondrial regulators, key regulators of β-oxidation, and negative influence on insulin response, providing a potential mechanism for exercise non-response.

Fragestellung: Die wachsende Prävalenz von Diabetes und Übergewicht rückt „Life-Style“-Interventionen als protektive und therapeutische Maßnahme vermehrt in den Fokus. Körperliche Aktivität ist eine der wirksamsten und nachhaltigsten Methoden um Diabetes zu verhindern, verzögern und zu behandeln. Allerdings sprechen verschiedene Individuen verschieden auf vergleichbare Trainingsprogramme an. Es gibt „High-Responder“, bei denen Sport die Glucosetoleranz und Insulinsensitivität verbessert, aber auch „Low-Responder“, die praktisch keinen metabolischen Nutzen davontragen.